Mutations in genetic loci that are important in autophagy (ATG16L1), the unfolded protein response (XBP1) and in innate immune sensing (NOD2) have been associated with inflammatory bowel diseases like Crohn's disease and ulcerative colitis. The autophagy protein ATG16L1 is recruited to the cell membrane by NOD1 and NOD2 at the site of bacterial invasion, thereby linking autophagy and NOD activation. Another cellular process that is linked to IBD and is closely related to autophagy is the unfolded protein response (UPR), which is induced by endoplasmic reticulum (ER) stress. However, whether there is a connection between the UPR and NOD1/2 innate immune signaling in IBD has thus far not been explored. The objectives of this application are to study the role of NOD activation within the UPR in the context of inflammatory bowel disease. Our central hypothesis is that ER stress in intestinal epithelial cells during IBD induces a pro-inflammatory response that is dependent on NOD1/2 signaling. We further propose that drugs that inhibit ER stress can alleviate IBD symptoms. Our hypothesis has been formulated based on strong preliminary data demonstrating that stimulation of Nod1/2-/- deficient bone marrow derived macrophages or injection of Nod1/2-/- mice with the ER stress inducer thapsigargin resulted in a significant decrease in IL-6 production compared to wild type controls. We plan to test this hypothesis by pursuing the following specific aims. Aim 1: Determine the role of the NOD1/2 signaling pathway for ER stress induced inflammation in the intestine. Aim 2: Determine whether pharmacological intervention of ER stress alleviates inflammation in models of IBD. Successful completion of the proposed work is of relevance to human health because it will elucidate the connection of ER stress in intestinal epithelial cells and the subsequent unfolded protein response and innate immune signaling via the NOD1/2 sensors in inflammatory bowel disease. The rationale of the proposed research is that elucidating the interaction between ER stress and NOD signaling during IBD will aid in the development of new and innovative approaches for treatment, which will be studied in this application. Successful completion of the proposed work will be significant because it will help us gain knowledge on the pathogenesis of IBD that may lead to the development of new intervention strategies.